Several studies indicate that women with breast cancer who undergo radiotherapy are susceptible to secondary lung cancer, whether they are smokers or nonsmokers. However, all studies to date have methodological limitations and have been small. Also, none have used molecular markers, which can improve exposure assessments or elucidate mediating mechanisms. Over time, radiotherapy methods have changed and doses to the lung have lessened. On the other hand, prevalence of smoking has increased among women in the western world. The identification of lung cancer risk is important in the context of the debates for benefits of radiation therapy in good prognosis tumors or older women. Thus, a study of breast and secondary lung cancer is needed to improve dosimetry assessments for radiation- induced lung cancer, with and without an interactive effect of smoking. Also, studying a unique population of women who have had both breast and lung cancer can provide new insights into carcinogeneis and cancer risk. In order to do this, we are proposing a population-based study using the Swedish Cancer Registry (SCR) and determination of radiation doses to the whole lung and side of the lung where the tumor subsequently develops. Reliable smoking data will be available. Our specific aims are to: 1) determine risk factors for secondary lung cancer in women treated with radiotherapy for breast cancer using complementary nested case-control and case-only study designs (n=559 cases and 559 matched controls); 2) to determine p53 inactivation pathways, (i.e., mutational spectra and loss of heterozygosity) in lung tumors of women with a prior history of breast cancer (n=402) and; 3) to determine the frequency of p53 inactivation pathways in breast tumors of women who did and did not develop lung cancer, and compare them to the frequency of p53 inactivation pathways in the lung tumors (n=342 cases and 342 controls). The first aim will allow us to identify risks. The second aim will provide information about the mechanistic relationship of radiotherapy to lung cancer and may identify a unique spectrum for radiation-related lung cancer. The third aim considers the combined occurrence of breast and lung cancer in a woman as phenotype of susceptibility for multiple primary cases. This study provides unique opportunities. Using the SCR and the unparalleled ability to obtain tissue blocks dating back to the 1950's, we can provide new data to understand risk in the context of molecular markers, especially because we will be able to retrieve the tumor blocks from both the breast and lung cancer from the same women. PERFORMANCESiTE(S) (organization,city,state) Lombardi Cancer Center Karolinska Institute Georgetown University Medical Center Department of Medical Epidemiology The Research Building Box 381 3970 Reservoir Road NW 19179 Stockholm Sweden Washington, DC 20007-2197 KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Dr. Peter Shields Georgetown University Medical Center, Washington, DC Dr. Per Hall Karolinska Institute, Sweden Dr. Giovanna Gagliardi Karolinska Institute, Sweden Dr. Balgit Singh Georgetown University Medical Center, Washington, DC Dr. Bassam Haddad Georgetown University Medical Center, Washington, DC Dr. Tim Jorgensen Georgetown University Medical Center, Washington, DC Dr. Frederik Granath Karolinska Institute, Sweden Dr. Melissa Bondy MD Anderson Cancer Center, Houston, TX Dr. Jo Freudenheim SUNY, University at Buffalo, Buffalo, NY Dr. Lois Travis National Cancer Institute, NIH, Bethesda, MD Dr. Goran Pershagen Karolinska Institute, Sweden Disclosure Permission Statement. Applicable to SBIR/STTR Only. See instructions. [] Yes [] No [unreadable] PHS 398 (Rev. 05/01) Page _2 I I[unreadable]= l/_.in_h I_AAI_IKI_ Niimh=r n=n_[unreadable] r'nn[unreadable]=_ilfiw=lw _f fh= hnffnm fhrnllnhnllf fh= _nnllr-ofinn n_ nnf i1[unreadable]= cllfflv_e the format shown below. Role on Project Principal Investigator Principal Investigator Co-Principal Investigator Investigator Investigator Investigator Investigator Consultant Consultant Consultant Consultant Form Page 2 [unreadable] erich _e "_ _.h [unreadable] Principal Investigator/Program Director (Last, first, middle): Shields, Peter G. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. Type density and size must conform to limits and specifications provided in the PHS 398 Instructions. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,